Chnical Radiology (1985) 36, 49%502 00(19-9260/85/496499502.00 © 1985 Royal College of Radiologists

Cholecystokinin Cholecystography: A Three Year Prospective Trial PAUL BYRNE*, GEORGE J. S. HUNTER and ALAN VALLON

Departments o f Radiology and Gastroenterology, Middlesex Hospital, London

A prospective study was undertaken to assess whether or not cholecystokinin cholecystography was able to predict the long-term results of cholecystectomy. The patients studied were all suffering from abdominal pain which was thought to be biliary in nature but in whom standard oral cholecystography did not reveal gall-bladder disease. There were 48 patients, mostly female, who were followed for 3 or more years after investigation and treatment. Half of the patients underwent cholecystec- tomy. There was no difference in outcome between those patients treated conservatively and those who underwent cholecystectomy. Cholecystokinin cholecystography was unable to predict the response of the patient to surgery in respect of relief of pain. It is concluded that chole- cystokinin cholecystography is not a useful investi- gation when considering whether or not chole- cystectomy would benefit the patient and afford lasting relief from pain.

The combination of cholecystography and ultrasound will usually identify most instances of gall-bladder disease. The patient who complains of 'typical biliary symptoms', in whom both investigations are normal, presents a clinical dilemma. It is possible that the origin of such patients' symptoms arises from the biliary tract, but that pathology is either not present or is unrecog- nised. That patients without evidence of gall-bladder or gall-stone disease are improved by cholecystectomy is well documented (Gunn et al., 1973; Reid and Rogers, 1975; Gough, 1977). It has been suggested that the use of cholecystokinin injected intravenously during cholecystography may help predict which patient will benefit from the operation (Nathan et al., 1970; Valberg et al., 1971; Freeman et al., 1975; Griffen et al., 1980; Sykes, 1982). Some of these studies have reported only short-term patient follow-up and doubt has been expressed about the value of cholecystokinin chole- cystography.

We have performed a prospective study in patients suspected of having gall-bladder disease without confir- matory evidence on initial investigation.

PATIENTS AND METHODS

Between April 1977 and October 1978 chole- cystokinin cholecystography was performed on 48

All correspondence to Dr G. J. S Hunter, Department of Radiology, The Middlesex Hospital, Mortimer Street, London Wl.

* Present address: Department of Radiology, The London Hospital, Whitechapel, London.

patients, all of whom presented with a typical history of biliary pain. All of these patients had undergone initial investigation by oral cholecystography and ultrasound which failed to demonstrate gall-stones. There were 43 females and five males. Their ages ranged from 19 to 69 years with a mean age of 46 years.

The patients were prepared as for a standard oral cholecystogram. All radiographs were exposed in the right posterior oblique projection with a focus-film dis- tance of 110 cm. The cholecystokinin cholecystogram started with a control exposure 1 min after infusion of 20 ml of normal saline into a peripheral vein via an indwelling cannula. A dose of cholecystokinin (Boots), 1 Ivy dog unit/kg, was then infused over 90 s. Radio- graphs were exposed at 1,2, 3, 5, 7, 10 and 15 min after the start of the infusion.

The test was clinically positive if the infusion of cholecystokinin reproduced the patient's symptoms. Radiographic abnormality was either morphological or functional. Morphological abnormality was diagnosed if a stricture was seen or if there was clear evidence of adenomyomatosis with Rokitansky-Aschoff sinuses. Functional abnormality was diagnosed if the gall-blad- der contracted by less than 35% by volume. This figure was derived from the degree of contraction defined in normal subjects by several groups of workers using stan- dard radiological or radionuclide techniques (Edholm, 1960; Englert and Chiu, 1966; Spellman et al., 1979). A report of the examination was sent to the referring clini- cian. The percentage change in volume during the examination was calculated wtih a digital computer (Apple II) coupled to a digitising graphics tablet using the formula:

Volumeoc Area3/%

Routine macroscopic and microscopic histological examination was made on all gall-bladder specimens removed at cholecystectomy.

Patient follow-up was by means of contact with the referring clinician or the general practitioner, plus a patient questionnaire in all cases.

Analysis of the data was undertaken using standard methods for comparing discrete variables, namely, the X 2 statistic. Correction for small numbers was made using Yates' method.

RESULTS

Follow-up information was available on all 48 patients. At the end of the study 25 patients remained symptomatic and 23 were asymptomatic. Twenty-four patients had undergone cholecystectomy and 24 were

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Table ! - Contingency table comparing the results of surgery with conservative management in all 48 patients (p>0.39)

No. of patients

Cholecysteetomy No cholecystectomy Totals

Symptomatic after 3 14 11 25 years

Asymptomatic after 3 10 13 23 years

Totals 24 24 48

Table 2 - Contingency table comparing the results of surgery with conservative management in 16 patients who had a normal cholecystokinin cholecystogram by all criteria (p>0.35)

No. ofpagen~

Cholecystectomy No cholecystectorny Totals

Symptomatic after 3 2 5 7 years

Asymptomatic after 3 1 8 9 years

Totals 3 13 16

Table 7 - Contingency table relating the outcome of choleeysteetomy with the histological appearances of the removed gall-bladder in the 24 patients who underwent surgery (p>0.65)

No. of patients

ChoIecystectomy No cholecystectomy Totals"

Symptomatic after 3 4 10 years

Asymptomatic after 3 2 8 years

Totals 6 18

14

10

24

treated conservatively. The results of the various subgroups are summarised in Tables 1-7; it will be noted that no p value is significant at the 5% level.

The histology of the removed gall-bladders revealed nine cases of adenomyomatosis, five cases of cholecystitis, two cases of cholesterosis and two cases of stricture formation. Six cases had normal histology.

Table 3 - (~ontingency table comparing the results of surgery with conservative management in 32 patients who had an abnormal cholecystokinin cholecystogram by any criteria (p>0.89)

No. of patients

Cholecystecorny No cholecystectomy Totals"

Symptomatic after 3 12 6 18 years

Asymptomatic after 3 9 5 14 years

Totals 21 11 32

CASE REPORTS

Case 1. M.F., a 52-year-old male, presented with recurrent upper abdominal pain of 4 years' duranon. During this period a right inguinal hernia had been repaired on two occasions without relief of pare. The pain was intermittent, often umbilical and without radiation. An oral cholecystogram was normal. The subsequent cholecystokmm pro- vocation cholecystogram revealed Rokitansky-Aschoff sinuses and a poorly contracting gall-bladder (Fig. 1) There was no pain ehcited by the test. Cholecystectomy was not performed and 5 years later the patient is pain free.

Table 4 - Contingency table comparing the results of surgery with conservative management in 16 patients who had an abnormal cholecystokinin cholecystogram by clinical criteria alone (p=l.0)

No. of patients

Cholecystecomy No cholecystectomy Totals

Symptomatic after 3 7 1 8 years

Asymptomatic after 3 7 l 8 years

Totals 14 2 16

Table 5 - Contingency table comparing the results of surgery with conservative management in 19 patients who had an abnormal choleeystokinin cholecystogram by functional criteria alone (P>0.7)

No. of patients

Cholecystecomy No cholecystectomy Totals

Symptomatic after 3 6 3 9 years

Asymptomatic after 3 6 4 10 years

Totals 12 7 19

Table 6 - Contingency table comparing the results of surgery with conservative management in 19 patients who had an abnormal eholecystokinin cholecystogram by morphological criteria alone (P>0.75)

No. of patients

Cholecystectorny No cholecystectomy Totals

Symptomatic after 3 9 years

Asymptomatic after 3 7 years

Totals 16

2 11

1 8

3 19 Fig. 1. - Case 1. Cholecystokinin provocation cholecystogram showing the prominent Rokitansky-Aschoff sinuses of adenomyomatosls.

CHOLECYSTOKININ CHOLECYSTOGRAPHY 501

Fig. 2 - Case 2 Cholecystokmm cholecystogram showing a stricture m the body of the gall-bladder and the resultant phrygian cap.

Case 2. A S , a 68-year-old female, presented with a 2-year history of recurrent upper abdominal pain. There had been 15 episodes during this period The pain was non-radiating and constant m nature. It was not related to food. There was associated flatulence but no nausea or vomiting. The imtial episode resulted in a period of jaundice No other relevant history was forthcoming. On examination there were no stigmas of liver disease and no abnormal physical signs Marked obesity was noted. Ultrasound mvesngation was normal. A cholecystokimn cholccystogram showed a stricture (Fig. 2). On this basis cholecystectomy was performed. Three months later the patient was pain free Prolonged follow-up revealed that after 3 years the pare had recurred and was identical in nature and severity to that before the cholecystectomy.

Case 3. A.C., a 48-year-old female, presented with a 2-year history of recurrent right upper quadrant pain. The pain occurred in bouts lasting up to 2 h, with radiation round to her back but with no relation to food. Nausea was associated with the attacks. No other relevant history was obtained. On examinanon there were no abnormal physi- cal signs. Ultrasound of the gall-bladder did not reveal stones and radiological invesngation of the abdomen was normal. A chole- cystokmin cholccystogram revealed a multilocular gall-bladder with poor contraction and stricture formanon (Fig. 3). A cholecystectomy was performed and pathological examination confirmed the presence of muscular strictures within the gall-bladder. After an imtial pain-free period of 2 months her symptoms recurred and have continued with httle change over the last 4 years

DISCUSSION

There are two components to the cholecystokinin provocation test: clinical and radiological. Chole- cystokinin produces contraction of the gall-bladder and relaxation of the sphincter of Oddi. Preparations of cholecystokinin available commercially for intravenous

Fig. 3 - Case 3. Cholecystokinin cholecystogram showing multiple strictures within the body of the gall-bladder.

use are less specific than the naturally occurring hor- mone and have a more widespread effect on gastroin- testinal motility. The effects of an intravenous injection of cholecystokinin were studied in 20 patients with irrita- ble bowel syndrome; injection resulted in increased col- onic motor activity in all of them (Harvey and Read, 1973). In addition, four of the eight patients in whom pain was related to food sustained a typical episode of their pain following the cholecystokinin injection. In 29 of 48 patients labelled as suffering with irritable bowel syndrome, distension of the ascending and transverse colon produced right-sided or upper abdominal pain (Swarbrick et al., 1980). Thus, in patients with food- related right upper quadrant pain the use of cholecystokinin cannot be expected to differentiate between the gall-bladder and the intestine as the site of origin for that pain.

There are several criteria which have been suggested as being indicative of abnormality during chole- cystokinin cholecystography, such as the demon- stration of spasm or a stricture in the neck or body of the gall-bladder, failure of adequate contraction of the gall-bladder and reproduction of the patient's pain (Nathan et al., 1970; Freeman et al., 1975; Griffen et al., 1980). In the present study we were unable to substantiate that the presence of any or all such abnor- malities predicted the eventual outcome of surgery. Despite the demonstration of histological changes of adenomyomatosis, this abnormality did not predict the long-term results of surgery. Case 1 illustrates the latter point, while Cases 2 and 3 illustrate that, even with clearly abnormal gall-bladders, cholecystectomy may not provide relief in the long term.

These findings are at variance with currently held opinion. A possible explanation is that we were able to follow our patients for over 3 years and, in some cases, up to 5 years. Many of the previous reports did not monitor patients for this length of time. As Cases 2 and 3 illustrate, an early relief of pain following cholecystec- tomy may not indicate lasting long-term relief.

In conclusion, some patients with biliary symptoms and normal investigations will be cured by cholecystec-

502 CLINICAL RADIOLOGY

tomy. We wish to state that cholecystokinin provocation during cholecystography does not provide any indica- tion as to whether surgical or conservative treatment should be followed in an attempt to alleviate the patient's symptoms.

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Englert, E. & Chiu, V (1966). Quantitative analysis of human biliary evacuation with radloisotoplc technique Gastroenterology, 50, 506-518

Freeman, J., Cohen, W. & Denbesten, L. (1975). Cholecystokinin cholangiography and analysis of duodenal bile in the investigation of pain in the right upper quadrant of the abdomen without gallstones. Surgery, Gynecology and Obstetrtcs, 140, 371-376.

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Harvey, R & Read, A. (1973). Effect of cholecystokinin on colonic motility and symptoms in patients with the irritable bowel syndrome. Lancet, i, 1-3.

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Reid, D. & Rogers, M. (1975). The negative cholecystogram in gallbladder disease. British Journal of Surgery, 62, 581-583

Spellman, S., Shaffer, E. & Rosenthall, L. (1979). Gallbladder empty- ing in response to cholecystokinin: a cholescintigraphlc study. Gastroenterology, 77, 115-120.

Swarbrick, E., Hegarty, J., Bat, L., Williams, C. & Dawson, A. (1980). Site of pain from the irritable bowel. Lancet, ii, 443-446.

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Valberg, L., Jabbari, M., Kerr, J., Curtis, A., Ramchand, S. & Prentice, R. (1971). Biliary pain in young women in the absence of gallstones. Gastroenterology, 60, 1020-1026.